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Cellular networks controlling T cell persistence in adoptive cell therapy

Nature Reviews Immunology volume 21, pages 769–784 (2021)Cite this article

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Abstract

The antitumour activity of endogenous or adoptively transferred tumour-specific T cells is highly dependent on their differentiation status. It is now apparent that less differentiated T cells compared with fully differentiated effector T cells have better antitumour therapeutic effects owing to their enhanced capacity to expand and their long-term persistence. In patients with cancer, the presence of endogenous or adoptively transferred T cells with stem-like memory or precursor phenotype correlates with improved therapeutic outcomes. Advances in our understanding of T cell differentiation states at the epigenetic and transcriptional levels have led to the development of novel methods to generate tumour-specific T cells — namely, chimeric antigen receptor T cells — that are more persistent and resistant to the development of dysfunction. These include the use of novel culture methods before infusion, modulation of transcriptional, metabolic and/or epigenetic programming, and strategies that fine-tune antigen receptor signalling. This Review discusses existing barriers and strategies to overcome them for successful T cell expansion and persistence in the context of adoptive T cell immunotherapy for solid cancers.

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Fig. 1: T cell subsets in infection, cancer and adoptive cell therapy.
Fig. 2: Methods to maintain T cell persistence and stemness.
Fig. 3: Enhancing resistance to immunosuppression and targeting metabolic pathways during adoptive cell therapy.

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Acknowledgements

The authors acknowledge funding support from the National Health and Medical Research Council of Australia (NHMRC), the Australian National Breast Cancer Foundation, the Cancer Council of Victoria and the ClearBridge Foundation. J.D.C. is supported by an Australian Government Research Training Program scholarship and a Peter MacCallum Cancer Foundation postgraduate scholarship. J.L. is a recipient of a US Cancer Research Institute Irvington postdoctoral fellowship (award no. 3530). A.K. is supported by an NHMRC senior research fellowship (APP1139607). P.A.B. is supported by an Australian National Breast Cancer Foundation fellowship (ECF-17-005) and a Victorian Cancer Agency Research fellowship (MCRF20011). P.K.D. is supported by an NHMRC senior research fellowship (APP1136680).

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Authors and Affiliations

  1. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Jack D. Chan, Junyun Lai, Clare Y. Slaney, Paul A. Beavis & Phillip K. Darcy

  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

    Jack D. Chan, Junyun Lai, Clare Y. Slaney, Paul A. Beavis & Phillip K. Darcy

  3. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia

    Axel Kallies

  4. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

    Axel Kallies

  5. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia

    Phillip K. Darcy

  6. Department of Immunology, Monash University, Clayton, Victoria, Australia

    Phillip K. Darcy

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The authors contributed equally to all aspects of the article. J.D.C. and J.L. contributed equally as first authors, and A.K., P.A.B. and P.K.D. contributed equally as senior authors.

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Chan, J.D., Lai, J., Slaney, C.Y. et al. Cellular networks controlling T cell persistence in adoptive cell therapy. Nat Rev Immunol 21, 769–784 (2021). https://doi.org/10.1038/s41577-021-00539-6

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